1. Field of the Invention
The invention relates to a method for inducing protection against the 4 serotypes of dengue fever in a patient, comprising:                (a) a first administration of a monovalent vaccine comprising a vaccinal virus of a first serotype of dengue fever,        (b) a second administration of a tetravalent vaccine comprising vaccinal viruses of the four serotypes of dengue fever, and        
in which the second administration (b) is made between at least 30 days and not more than 12 months after the first administration (a).
2. Summary of the Related Art
Dengue fevers are caused by four viruses of the flavivirus genus which are of similar serological type but differ from the antigen point of view (Gübler et al., 1988, in: Epidemiology of arthropod-borne viral disease. Monath T P M, editor, Boca Raton (Fla.): CRC Press: 223-60; Kautner et al., 1997, J. of Pediatrics, 131: 516-524; Rigau-Pérez et al., 1998, Lancet, 352: 971-977; Vaughn et al., 1997, J. Infect. Dis., 176: 322-30). Infection with a serotype of dengue fever may produce a spectrum of clinical disease from non-specific viral syndrome to severe fatal hemorrhagic disease. The incubation period for dengue fever after a mosquito bite is approximately 4 days (from 3 to 14 days). Dengue fever is characterized by a two-phase fever, headaches, pains in various parts of the body, prostration, eruptions and lymphadenopathy (Kautner et al., 1997, J. of Pediatrics, 131: 516-524; Rigau-Pérez et al., 1998, Lancet, 352: 971-977). The viremic period is of the same as the febrile period (Vaughn et al., 1997, J. Infect. Dis., 176: 322-30). Cure of dengue fever is complete after 7 to 10 days, but prolonged asthenia is normal. Reduced leukocyte and platelet numbers frequently occur.
Hemorrhagic dengue fever is a severe febrile disease characterized by homeostasis abnormalities and an increase in vascular permeability which can lead to hypovolemia and hypotension (dengue fever with shock syndrome), often complicated by severe internal bleeding. The mortality rate for hemorrhagic dengue fever can reach 10% without treatment, but is ≦1% in most centers with experience of treatment (WHO Technical Guide, 1986. Dengue hemorrhagic fever: diagnosis, treatment and control, p. 1-2. World Health Organization, Geneva, Switzerland).
Routine laboratory diagnosis of dengue fever is based on isolation of the virus and/or the detection of antibodies specific to dengue fever virus.
Dengue is the second most important infectious tropical disease after malaria, more than half of the world's population living in areas where there is a risk of epidemic transmission. There are estimated to be 50-100 million cases of dengue fever every year, 500,000 patients hospitalized for hemorrhagic dengue fever, and 25,000 deaths. Dengue fever is endemic in Asia, the Pacific, Africa, Latin America and the Caribbean. Dengue fever virus infections are endemic in more than 100 tropical countries and hemorrhagic dengue fever has been documented in 60 of these countries (Gubler, 2002, TRENDS in Microbiology, 10: 100-103; Monath, 1994, Proc. Natl. Acad. Sci., 91: 2395-2400). A number of well-described factors would appear to be implicated in dengue fever—population growth, unplanned and uncontrolled urbanization, in particular associated with poverty, an increase in air travel, lack of effective mosquito control and deterioration of sanitary and public health infrastructure (Gubler, 2002, TRENDS in Microbiology, 10: 100-103). Travellers and expatriates are increasingly being warned about dengue fever (Shirtcliffe et al., 1998, J. Roy. Coll. Phys. Lond., 32: 235-237). Dengue fever has been one of the main causes of febrile diseases among American troops during deployments in tropical areas where dengue fever is endemic (DeFraites et al., 1994, MMWR, 1994, 43: 845-848).
The viruses are maintained within a cycle involving humans and Aedes aegypti, a domestic mosquito which bites during the daytime, and prefers to feed on man. Infection in man is initiated by injection of the virus during the blood meal of an infected Aedes aegypti mosquito. The salivary virus is mainly deposited in the extravascular tissues. The first category of cells to be infected after inoculation are the dentritic cells, which then migrate to the lymphatic ganglia (Wu et al., 2000, Nature Med., 7: 816-820). After initial replication in the skin and lymphatic ganglia, the virus appears in the blood in the course of the acute febrile stage, generally for 3 to 5 days.
Along with the dentritic cells, monocytes and macrophages are among the first targets of dengue fever virus. Protection against homotypic reinfection is complete and probably lasts a lifetime, but cross-protection between the different types of dengue lasts from less than a few weeks to a few months (Sabin, 1952, Am. J. Trop. Med. Hyg., 1: 30-50). As a consequence, an individual may become infected with a different serotype. A second infection due to dengue fever is in theory a risk factor for the development of severe dengue fever. However, hemorrhagic dengue fever is multifactorial—factors include the strain of virus involved and the age, immune status and genetic predisposition of the patient. Two factors play a major role in the occurrence of hemorrhagic dengue fever—rapid viral replication with a high level of viremia (the severity of the disease being associated with the level of viremia; Vaughn et al., 2000, J. Inf. Dis., 181: 2-9) and a major inflammatory response with the release of high levels of inflammatory mediators (Rothman and Ennis, 1999, Virology, 257: 1-6). There is no specific treatment against dengue fever. Treatment for dengue fever is symptomatic, with bed rest, control of the fever and pain through antipyretics and analgesics, and adequate drinking. The treatment of hemorrhagic dengue fever requires balancing of liquid losses, replacement of coagulation factors and the infusion of heparin.
Preventive measures are currently based on control of the vector and personal protection measures which are difficult to apply and are costly. No vaccine against dengue fever has at present been approved. Given that the four serotypes of dengue fever are in circulation in the world and that they have been reported as being involved in cases of hemorrhagic dengue fever, vaccination should ideally confer protection against the four serotypes of dengue fever virus.
When immunizing with a tetravalent vaccine, it may happen that the response is induced predominantly against only one or at most 3 serotypes. There is therefore a need for a method which makes it possible to reduce interference between the different serotypes and makes it possible to induce neutralizing antibodies against the 4 serotypes of dengue fever.